Transcript Al Chemistry Project Chung Po Wai 7S (10) So Ying Kin 7S (20)

Drug Development ——
Metformin
Diabetes type1 vs type2
Type 1 diabetes
Insulin-dependent
 Caused by the failure of pancreas to
produce enough insulin

Type2 diabetes
Insulin-independent
 Caused by the failure of liver and
muscle cells to respond to the insulin
 Due to lack of receptor molecules that
bind to insulin

Introduction
Metformin (N,N-dimethylimidodicarbonimidic diamide) is
believed to be the most widely prescribed anti-diabetic
drug in the world.
- First choice in the treatment for type 2 diabetes.
Function
． Suppress hepatic glucose production
． Increase insulin sensitivity
． Enhance peripheral glucose uptake
． Increase fatty acid oxidation
． Decrease absorption of glucose from the
gastrointestinal tract
Lead Compound Discovery
1922 ---first discovered as a product in the synthesis of
N,N-dimethylguanidine. (Emil Werner and James Bellandin)
1929 --- found to reduce blood sugar
1929-1949 --- research stopped
1950 --- found not to decrease blood pressure and heart rate in
animals
1950 --- a physician, Garcia, used it to treat influenza and
discovered it can lower the blood sugar to minimum
physiological limit and it is non-toxic.
a French diabetologist Jean Sterne tried to re-investigate
the blood sugar lowering activity of metformin
Molecular modification
1.
2.
3.
4.
5.
Galega officinalis (Goat’s rue) was
used for diabetes treatment.
But it was found to be too toxic
Then phenformin derived from
Galega officinalis was used.
But it was still not safe for human use.
Finally metformin which has similar
structure to phenformin was used
and it is much less toxic.
Galega officinalis flowers
Structure of phenformin and metformin
Metformin
Phenformin
They both are the members of biguanide and the
its structure is shown below:
Formulation development
In diabetes treatment, metformin can:
． decrease glucose (sugar) production in the liver
． decreas absorption of glucose by the intestines
However, metformin also need to use with some other
drugs. Here’s some examples:
Repaglinide
Pioglitazone
Rosiglitazone
Sitagliptin
Repaglinide can:
- lower blood glucose by stimulating the
release of insulin from the pancreas
Pioglitazone can:
 reduce
insulin resistance in the liver and
peripheral tissues
 increase the expense of insulindependent glucose
 decrease withdrawal of glucose from the
liver
 reduce quantity of glucose, insulin and
glycated haemoglobin in the
bloodstream
Rosiglitazone can:
act as insulin sensitizers
 reduce glucose, fatty acid, and insulin
blood concentrations
 lower insulin resistance

sitagliptin can:

work to competitively inhibit the enzyme
dipeptidyl peptidase 4 (DPP-4)
 Prevent the break down of GLP-1 and
GIP hormones.
 these hormones are then able to
potentiate the secretion of insulin and
suppress the release of glucagon by the
pancreas
Safety test and human trials
Response to all diabetic therapies should be
monitored by periodic measurements of fasting
blood glucose and glycosylated hemoglobin
Levels
Initial and periodic monitoring of hematologic
parameters, such as hemoglobin, hematocrit and red
blood cell indices, and renal function should be
performed
Human trials:
Most Common Adverse Reactions (> 5.0 %) in a Placebo-Controlled
Clinical Study of Metformin Hydrochloride Tablets Monotherapy
Adverse Reaction
Diarrhea
Nausea/Vomiting
Flatulence
Asthenia
Indigestion
Metformin
Hydrochloride Tablets
Placebo (n = 145)
Monotherapy (n = 141)
% of Patients
53.2
11.7
25.5
8.3
12.1
5.5
9.2
5.5
7.1
4.1
Abdominal Discomfort
6.4
4.8
Headache
5.7
4.8
Pediatric Patients:
Metformin hydrochloride tablets USP ：
．effectively lower glucose levels in children (ages
10 to 16 years) with type 2 diabetes
．have not been studied in children younger than
10 years old.
Special conditions:
．have kidney problems
．have liver problems
．have heart failure that is treated with medicines, such as digoxin
or furosemide
．drink a lot of alcohol. This means you binge drink for short
periods or drink all the time
．are seriously dehydrated (have lost a lot of water from your body)
．are going to have an x-ray procedure with injection of dyes
(contrast agents)
．develop a serious condition, such as heart attack, severe
infection, or a stroke
Approval for marketing
．described in 1957 and became available in the
British National Formulary in 1958.
．first marketed in France in 1979, but did not
receive approval by the U.S. Food and Drug
Administration (FDA) for Type 2 diabetes until
1994.
1995 - March 3 - New molecular entity (NME)
2000- October 13 - New formulation
2003- September 11 - New formulation
2004- April 28 - New formulation
2005- June 3 - New manufacturer
2008 - October 20 - New formulation
THE END